Copyright is owned by the Author of the thesis. Permission is given for
a copy to be downloaded by an individual for the purpose of research and
private study only. The thesis may not be reproduced elsewhere without
the permission of the Author.
The Bisspiroketal Moiety of epi-17-Deoxy-(0-8)-salinomycin.
A thesis presented in partial fulfilment of the requirements for the degree of
Doctor of Philosophy at Massey University.
Geoffrey Martyn Williams.
November 1991
Massey University Library Thesis Copyright Form
. . ;ire
B1$p1 roke:fol fllo, el�of
Title of thesis: e..pi -17-
Oeo�-
( 0-3)-8::ilino��;
n(1) (a)
I
give permission for my thesis to be made available to readers in Massey University Library under conditions determin'ed by the Librarian.�
do not wish my thesis to be made available to readers without my written consent for ... months.(2) (a)
I
agree that my thesis, or a copy, may be sent to another institution under conditions determined by the Librarian.�·I
do not wish my thesis, or a copy, to be sent to another institution without my written consent for months.(3)
(a)I
agree that my thesis may be copied for Library use.�
do not wish my thesis to be copied for Library use for ... months.Sign
U
·_..,/ S ��
Date ?�-- Tl-4 I
The copyright of this thesis belongs to the author. Readers must sign their name in the space below to show that they recognise this. They are asked to add their permanent address.
NMIE AND ADDRESS DATE
15
--- -- � -�--- - · ·-·
MA"SSEY UNIVERSITJ\
l!SR.t\RY
To my family for their support and patience.
Acknowledgements.
I wish to express my sincere thanks to Dr. Margaret Brimble who, in her role as supervisor, has provided me with invaluable assistance, guidance and encouragement throughout the course of this work. In addition, she has introduced me to an area of research that has proved stimulating, thought-provoking and immensely rewarding and for this I am extremely grateful.
I would also like to acknowledge the support provided by my eo-supervisor Assoc.
Professor Ken Jolley, who has also introduced me to the intricacies of high field nuclear magnetic resonance spectroscopy.
It remains for me to thank Dr. Mark Brimble for his assistance in proof reading this thesis, and especially my friend and colleague Michael Nairn who, in addition to helping with the proof reading, has made life in the laboratory bearable when things became a little trying.
Finally I wish to acknowledge Professor Ray Baker of Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex, for the gift of chemicals which made a significant portion of this work possible.
Abstract.
The synthesis of 2-(3,4-epoxy-3-methylbutan-1-yl)-1 ,7 -dioxaspiro[S.S]undec-4-ene 188 is described, the key step in it's formation being an addition of the lithium acetylide derivative of S-tert-butyldiphenylsilyloxy-2-methyl-2-trimethylsilyloxy-7 -octyn-1-p
toluenesulphonate 182 to o-valerolactone. The epoxide 188 was then converted to the hydroxy spiroketal 4-(1,7-dioxaspiro[S.S]undec-4-en-2-yl)-2-methyl-2-butanol 149 which underwent a Barton-type oxidative cyclisation to afford both the cis- and trans-2,2-dimethyl- 1,6,8-trioxadispiro[ 4.1.S.3]pentadec-13-enes 192 and 152. The ring system of this latter compound is analogous to the unsaturated bisspiroketal present in the polyether antibiotic epi-17-deoxy-(0-8)-salinomycin 8.
Subsequently the route was modified to afford the trans- and cis-(2-methyl-1,6,8- trioxadispiro[4.1.S.3]pentadec-13-en-2-yl)methanols 211-214, since it was expected this terminal hydroxyl group would provide a 'handle' by which these molecules could be further elaborated. This required conversion of the epoxide 1 8 8 to 4-(1,7- dioxaspiro[S.S]undec-4-en-2-yl)-1-iodo-2-methyl-2-butanol 200, which was followed by a Barton-type oxidative cyclisation, to give the cis- and trans-2-iodomethyl-2-methyl-1,6,8- trioxadispiro[4.1.S.3]pentadec-13-enes 201-204, which were then converted to the alcohols 211-214.
The techniques used to construct these relatively simple bisspiroketal analogues were then applied to an enantioselective synthesis of the bisspiroketal portion of epi-17 -deoxy-(0- 8)-salinomycin. The two key intermediates required for this were (l'S, 3R, SS, 6S)-(+)-6- [1'-(tert-butyldiphenylsilyloxymethyl)propyl]-3,S-dimethyl-tetrahydropyran-2-one 84 and (SR, 2S)- and (SS, 2S)-2-methyl-2,S-bis(trimethylsilyloxy)-7-octyn-1-p-toluenesulphonate 231. The lactone 84 was prepared, using Evans' directed aldol methodology, from (4R, SS)-(+ )-4-methyl-3-(1'-oxobutyl)-S-phenyloxazolidin-2-one 219 and (S)-( + )-2,4-dimethyl- 4-pentenal 218. The acetylene 231 was prepared from levulinic acid 174, and the procedure incorporated a resolution step which enabled the 2S configuration of 231 to be introduced. The lactone 84 and the the lithium acetylide derivative of acetylene 231 were combined and subsequently converted to the (1"S, 2S, 2'S, 6'R, 8'S, 9'S, ll'R)-(-)- and (l"S, 2S, 2'R, 6'R, 8'S, 9'S, ll'R)-(+)-4-{8-[1-(tert-butyldiphenylsilyloxymethyl)propyl]
-9,11-dimethyl-1,7 -dioxaspiro[S.S]undec-4-en-2-yl}-1-iodo-2-methyl-2-butanols 245 and 246. These hydroxy spiroketals were transformed, again using the Barton-type oxidative cyclisation methodology, to the cis-(l'S, 2S, SR, 7S, 9S, lOS, 12R)-(-)- and the trans
(l'S, 2S, SS, 7S, 9S, lOS, 12R)-(-)-9-[l-(tert-butyldiphenylsilyloxymethyl)propyl]-2- iodomethyl-2,10,12-trimethyl-1 ,6,8-trioxadispiro[ 4.1.S.3]pentadec-13-ene 248 and 247, the latter of which resembles precisely the corresponding portion of epi-17-deoxy-(0-8)
salinomycin. In addition, the termini of the bisspiroketal 247 are selectively functionalised, which will allow further elaboration to the entire natural product 8.
The synthesis of the cis- and tra n s - 2 , 2 - d i m e t h y l - 1 S - h y dr o x y-1 , 6 , 8 - trioxadispiro[4.1.S.3]pentadec-13-enes 156 and 159, and of cis-2,2-dimethyl-13-hydroxy- 1,6,8-trioxadispiro[4.1.S.3]pentadec-14-ene 268 is described. These were formed firstly by allylic bromination of the cis- and trans-2,2-dimethyl-1,6,8-trioxadispiro[4.1.S.3]pentadec- 13-enes 192 and 152 to give the cis- and trans-1S-bromo- 2 , 2- dimethyl-1,6,8- trioxadispiro[ 4.1.S. 3 ]pentadec-13-enes 262 and 265, and cis-13-bromo-2,2-dimeth y l- 1,6,8-trioxadispiro[4.1.S.3]pentadec-14-ene 261. These bromides were then displaced by an oxygen nucleophile to afford the alcohols 268, 156, 159, a procedure which involved both SN2 and anti-SN2' processes.
Chapter 1
Chapter 2
Contents.
Introduction.
1 . 1
1 .2 Biosynthesis of Polyether Antibiotics.
1 .3 Total Syntheses of Salinomycin and Narasin by Kishi et al.
1 .4 The Total Synthesis of Salinomycin by Yonemitsu et al.
1 .5 Synthesis of Tricyclic Bisspiroketals.
Synthesis of 1 .6.8-Trioxadispiro[ 4. 1.5.3lpentadec- 13-ene Ring Systems.
2 . 1 Retrosynthesis and Synthetic Strategy.
2.2 Synthesis of the Cyclisation Precursor 4-( 1',7'-Dioxa spiro[5.5]undec-4'-en-2'-yl)-2-methyl-2-butanol 149.
2.3 Synthesis of 2,2-Dimethyl- 1 ,6,8-trioxadispiro
[ 4.1 .5.3]pentadec- 13-ene 152, 192.
2.4 Synthesis of the Cyclisation Precursor 4-(1',7'- Dioxaspiro[5.5]undec-4'-en-2'-yl)- 1-iodo-2-methyl-2- butanol 200.
2.5 Synthesis of the (2'-Methyl- 1',6',8'-trioxadispiro
Page
1 5
1 1 27 37
43
44
5 1
58
[ 4. 1 .5.3]pentadec- 13'-en-2'-yl)methanols 211-214. 60
Chapter 3
Chapter 4
Chapter 5
Synthesis of the Bisspiroketal Moiety of eQi-17-Deoxy-(0-8)- salinomycin.
3.1 The Optically Active Lactone 84.
3.2 Enantioselective Synthesis of the Cyclisation Precursors 245, 246.
3.3 Assembly of the Bisspiroketal Moiety of epi-17 -Deoxy-(0-8)-salinomycin.
3.4 Summary.
4.1 Allylic Oxidation of 2,2-Dimethyl-1,6,8-trioxa dispiro[ 4.1.5.3]pentadec-13-ene.
4.2 Summary.
Experimental
References
72
77
84 99
102 110
112
143
Abbreviations.
AIBN = 2,2'-azobisisobutyronitrile
ax = axial
Bzl = benzyl
cat. = catalytic
COSY = correlation spectroscopy
CSA = camphorsulphonic acid
DDQ = 2,3-dichloro-5, 6-dicyano-1 ,4-benzoquinone
DHP = dihydropyranyl
DIBAL = diisobutylaluminium hydride
DMAP = 4-dimethylaminopyridine
DMF = N, N-dimethylformamide
DMSO = dimethylsulphoxide
eq = equatorial
equiv. = equivalent
HET COR = heteronuclear correlation spectroscopy
imid = imidazole
MCPBA = meta-chloroperoxybenzoic acid
Ms = methanesulphonyl
NBS = N-bromosuccinimide
NCS = N-chlorosuccinimide
NMO = N-methylmorpholine-N-oxide
nmr = nuclear magnetic resonance
PCC = pyridinium chlorochromate
PPTS = pyridinium p-toluenesulphonate
Py = pyridine
RT = room temperature
Tf = trifluoromethanesulphonyl
1FA = trifluoroacetic acid 1FAA = trifluoroacetic anhydride
THF = tetrahydrofuran
THP = tetrahydropyrany 1
tic = thin layer chromatography
TMS = trimethylsilyl
Ts = p-toluenesulphonyl
TSA = p-toluenesulphonic acid
